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Nuclear hormone receptor antagonism with AP-1 by inhibition of the JNK pathway

AuthorsCaelles, Carme; González-Sancho, José Manuel ; Muñoz Terol, Alberto
Nuclear hormone receptors
Protein phosphorylation
Signal transduction
Issue Date15-Dec-1997
PublisherCold Spring Harbor Laboratory Press
CitationGenes and Development 11(24): 3351-3364 (1997)
AbstractThe activity of c-Jun, the major component of the transcription factor AP-1, is potentiated by amino-terminal phosphorylation on serines 63 and 73 (Ser-63/73). This phosphorylation is mediated by the Jun amino-terminal kinase (JNK) and required to recruit the transcriptional coactivator CREB-binding protein (CBP). AP-1 function is antagonized by activated members of the steroid/thyroid hormone receptor superfamily. Recently, a competition for CBP has been proposed as a mechanism for this antagonism. Here we present evidence that hormone-activated nuclear receptors prevent c-Jun phosphorylation on Ser-63/73 and, consequently, AP-1 activation, by blocking the induction of the JNK signaling cascade. Consistently, nuclear receptors also antagonize other JNK-activated transcription factors such as Elk-1 and ATF-2. Interference with the JNK signaling pathway represents a novel mechanism by which nuclear hormone receptors antagonize AP-1. This mechanism is based on the blockade of the AP-1 activation step, which is a requisite to interact with CBP. In addition to acting directly on gene transcription, regulation of the JNK cascade activity constitutes an alternative mode whereby steroids and retinoids may control cell fate and conduct their pharmacological actions as immunosupressive, anti-inflammatory, and antineoplastic agents.
Description15 pages, 9 figures.
Publisher version (URL)http://dx.doi.org/10.1101/gad.11.24.3351
Appears in Collections:(IIBM) Artículos
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